The Coronavirus outbreak has posed a great threat to human health. Facing the continuous mutation of Coronavirus, researchers are working hard to develop effective and broad-spectrum anti-COVID-19 drugs as well as vaccines. At the end of 2021, some small-molecule oral drugs were approved for marketing with excellent clinical data, bringing a glimmer of hope for humanity’s victory over the epidemic. In this paper, the research and development progress of small molecule therapeutics is reviewed based on literature and database.
Differing from neutralizing antibodies blocking the virus surface proteins, small molecule drugs in development focus on the inhibition of virus transfection process (mainly intracellular). They have the advantages of quick mass production for urgent supply, low cost, good accessibility, and are suitable for most people. According to statistics, there are nearly 200 small molecule compounds currently in clinical trials while some breakthroughs have already been made, including Remdesivir, Paxlovid, Molnupiravir, and S-217622.
Remdesivir
Remdesivir is a cyano-replaced prodrug of adenosine nucleotide analogues, originally produced by Gilead. It is transformed into nucleoside triphosphate in vivo and can be competitively incorporated into the RdRp catalytic pocket of viruses. Then it is incorporated into the newly synthesized RNA as virus RdRp substrates, which can interrupt the synthesis of viral genome so as to achieve the effect of inhibition.
In February 2020, a joint research team of Wuhan Institute of Virology and Academy of Military Medical Sciences found that 50% effective concentration (EC50) of remdesivir inhibiting coronavirus replication in vitro reaches 0.77μmol/L. In the early days of the epidemic, remdesivir gathered increasing attention when a small number of cases treated with it in the United States recovered quickly.
On April 25, 2022, FDA extended the approval for remdesivir application for child patients (older than 28 days, weight more than 3 kg), targeting those hospitalized children or non-hospitalized children who have mild to moderate symptoms with a high risk of disease progression. Remdesivir became the first drug approved for the treatment of COVID-19 in children under 12 years old.
Paxlovid（Nirmatrelvir/Ritonavir）
Paxlovid is composed of coronavirus 3CLpro inhibitor Nirmatrelvir (PF-07321332) and antiviral drug ritonavir, developed by Pfizer. Nirmatrelvir can block RNA replication of the virus by stopping the activity of coronavirus 3CLpro. A low dose of Ritonavir can help slow the metabolism or degradation of nirmatrelvir, keeping it active in the body longer and helping to fight the virus more effectively.
On December 15, 2021, Pfizer announced the results of a new clinical trial that paxlovid can significantly reduce the risk of hospitalization or death in the treatment of patients. The final analysis report of clinical trials conducted in COVID-19 patients who are likely to develop severe symptoms showed that 0.7% (5/697) of patients in the paxlovid group who received treatment within 3 days of symptom onset required hospitalization and none died. 6.5% (44/682) of patients in the placebo group required hospitalization, and nine patients later died. Paxlovid reduced the risk of hospitalization or death in this cohort by 89%. Among patients treated within 5 days of symptom onset, 0.8% (8/1039) of them in the paxlovid group required hospitalization and none died. 6.3% (66/1046) of patients in the placebo group required hospitalization, and 12 patients later died. To sum up, paxlovid reduced the risk of hospitalization or death by 88% in this trial.
On December 22, 2021, the US FDA granted the emergency use authorization for Paxlovid for the treatment of adults and children (aged 12 years older, weighing at least 40 kg) with mild to moderate COVID-19 symptoms. In addition, Pfizer announced that in vitro biochemical tests showed that nirmatrelvir has a potent inhibitory effect against Omicron variant 3CLpro, with enormous potential to fight against Omicron variants.
Molnupiravir
Molnupiravir is a nucleoside analogue jointly developed by Merck and Ridgeback, which is hydrolyzed into the prototype drug EIDD-1931 after entering human body. The drug acts as an RdRp inhibitor, preventing the virus from replicating by replacing normal ribonucleotides.
On November 4, 2021, Molnupiravir was approved for the first time in the UK for the treatment of adults who have mild to moderate COVID-19 symptoms and have a high risk of hospitalization. On December 23, 2021, the U.S. FDA granted Molnupiravir emergency use authorization primarily for the treatment of adult patients who have directly tested positive for SARS-COV-2 and have underlying risks of severe illness. These patients usually have no access to other FDA-approved alternative therapeutics for COVID-19 or these treatment strategies are clinically unavailable for them.
Related Products:
| Targets | Name | CAS | Synonyms | Description |
| SARS-CoV;SARS-CoV-2 | Remdesivir | 1809249-37-3 | GS-5734; 2-ethylbutyl (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate | Remdesivir, an analog nucleotide inhibitor, with effectively antiviral activity in vitro against various virus. |
| SARS-CoV-2;HIV | Ritonavir | 155213-67-5 | Norvir; ABT-538; A-84538; 538, ABT; ABT 538; ABT-538; ABT538; Abbott 84538 | Ritonavir is an HIV protease inhibitor. |
| SARS-CoV-2 | Molnupiravir | 2492423-29-5 | EIDD-2801; MK-4482; β-D-N4-hydroxycytidine-5′-isopropyl ester | Molnupiravir derived from a N(4)-hydroxycytidine, is an orally bioavailable broad spectrum antiviral compound that is effective against SARS-CoV2 infection. |